Nitric oxide decontamination of the upper respiratory tract

ABSTRACT

A method of topically treating the respiratory tract of a mammal with nitric oxide exposure includes the steps of providing a source of nitric oxide containing gas and delivering the nitric oxide containing gas nasally to the upper respiratory tract of the mammal. Also provided are several designs for a nasal delivery device for the controlled nasal deliver the nitric oxide containing gas.

CLAIM OF PRIORITY

This application is a divisional of U.S. patent application Ser. No.11/107,168, filed on Apr. 14, 2005, which is a continuation-in-part ofU.S. patent application Ser. No. 11/021,109, filed on Dec. 23, 2004,which is a continuation-in-art of U.S. application Ser. No. 10/944,479,filed Sep. 17, 2004, which is a continuation of U.S. application Ser.No. 10/172,270, filed Jun. 14, 2002 and issued as U.S. Pat. No.6,793,644, which in turn is a continuation of U.S. application Ser. No.09/749,022, filed on Dec. 26, 2000 and issued as U.S. Pat. No.6,432,077. The above patents and patent applications are incorporated byreference as if set forth fully herein.

FIELD OF THE INVENTION

The field of the invention relates to devices and methods for topicallytreating the upper respiratory tract of a mammal. More specifically, itrelates to devices and methods for controlled delivery of the nitricoxide containing gas nasally to the upper respiratory tract of themammal to topically treat the respiratory tract and to decontaminate theupper respiratory tract of microorganisms.

BACKGROUND OF THE INVENTION

The upper respiratory tract is the entrance port for microorganismsentering the lower respiratory tract, i.e., the lungs of a subject. Theupper respiratory tract frequently traps these microorganisms and maykill them before they effectively enter the body. However, if themicroorganism is able to get a foothold in the upper respiratory tract(e.g., a common cold virus), it is possible that the virus maythereafter move into the lungs. Additionally, the existence orpersistence of microorganisms in the upper respiratory tract may lowerthe immune system so that the lungs become susceptible to anothermicroorganism such as bacteria that may cause a bacterial pneumonia orother infection. Therefore, targeted therapeutic or preventativetreatment of the upper respiratory tract would speed the recovery fromlocal infections or preclude the progression to an infection in thelungs or other related systems.

The link between upper respiratory tract infections and the lowerrespiratory tract is well documented. For example, the followingarticles, each herein incorporated by reference in their entirety,support the proposition that treating the upper respiratory tract hasbeneficial value to the lungs and lower respiratory tract. Papadopoulos,et al. “Rhinoviruses infect the lower airways.” J. Infect. Dis. 2000;181:1875-1884; Gem J. E. “Viral respiratory infection and the link toasthma.” Pediatr. Infect. Dis. J. 2004; 23 (Suppl. 1):S78-S86; Fraenkel,et al “Lower airway inflammation during rhinovirus colds in normal andin asthmatic subjects.” Am. J. Respir. Crit. Care Med. 1995:151:879-886; and Pizzichini, et al. “Asthma and Natural Colds.Inflammatory Indices in Induced Sputum: A Feasibility Study.” Am J.Respir. Crit. Care Med. 1998; 158:1178-84.

The treatment of the upper respiratory tract has focused primarily ontraditional pharmaceuticals, such as orally consumed antibiotics. In the1980's, it was discovered by researchers that the endothelium tissue ofthe human body produced nitric oxide (NO), and that NO is an endogenousvasodilator, namely, an agent that widens the internal diameter of bloodvessels. NO is most commonly known as an environmental pollutant that isproduced as a byproduct of combustion. At low concentrations,researchers have discovered that inhaled NO can be used to treat variouspulmonary diseases in patients. For example, NO has been investigatedfor the treatment of patients with increased airway resistance as aresult of emphysema, chronic bronchitis, asthma, adult respiratorydistress syndrome (ARDS), and chronic obstructive pulmonary disease(COPD). NO has also been shown to have anti-microbial and/or microcidalactivity over a broad range of microorganisms.

While NO has shown promise with respect to certain medical applications,delivery methods and devices must cope with certain problems inherentwith gaseous NO delivery. First, exposure to high concentrations of NOmaybe toxic, especially exposure to NO in concentrations over 1000 ppm.Even lower levels of NO, however, can be harmful if the time of exposureis relatively high. For example, the Occupational Safety and HealthAdministration (OSHA) has set respiratory tract exposure limits for NOin the workplace at 25 ppm time-weighted averaged for eight (8) hours.

Another problem with the delivery of NO is that NO rapidly oxidizes inthe presence of oxygen to form NO₂, which is highly toxic, even at lowlevels. If the delivery device contains a leak, unacceptably high levelsof NO₂ gas can develop. In addition, to the extent that NO oxidizes toform NO₂, there is less NO available for the desired therapeutic effect.The rate of oxidation of NO to NO₂ is dependent on numerous factors,including the concentration of NO, the concentration of O₂, and the timeavailable for reaction. Since NO will react with the oxygen in the airto convert to NO₂, it is desirable to have minimal contact between theNO gas and the outside environment.

Accordingly, there is a need for a device and method for the topicaltreatment of upper respiratory tract by the administration of gaseousNO. The delivery must be take into account subject respiration, comfort,and safety. In addition, delivery methods and devices may be designed totarget delivery of the NO gas to the upper respiratory region of thepatient without allowing the introduction of NO to the lungs.

SUMMARY OF THE INVENTION

One embodiment of the invention is a method of topically treating arespiratory tract of a mammal with nitric oxide exposure comprising thesteps of: (1) providing a source of nitric oxide containing gas; and (2)nasally delivering the nitric oxide containing gas, wherein the nitricoxide containing gas is confined to an upper respiratory tract of themammal. The upper respiratory tract includes the nasal cavities, sinusesand nasopharynx. Another embodiment is a method of topicallydecontaminating an upper respiratory tract of microorganisms with nitricoxide exposure comprising the same two steps. The microorganisms mayinclude, but is not limited to, bacteria, viruses, fungi, and parasites.Another embodiment is a method of bathing an upper respiratory tract ofa mammal with nitric oxide containing gas comprising the same two steps.

Several delivery mechanisms correlate the administration of the NOcontaining gas with either the patient's inhalation or exhalation.Additionally, delivery may be correlated to the patient's nasal or oralbreathing. The delivery methods act to isolate the NO containing gaswithin the upper respiratory tract of the mammal. The nasal delivery mayalso coincide with a deceleration of the mammal's nasal inhalation. Thedelivery may occur at a predetermined time after a detection of amammal's inhalation or at a predetermined time after a detection of amammal's exhalation.

The concentration of nitric oxide in the nitric oxide containing gas maybe about 120 ppm to about 400 ppm, preferably, about 160 ppm to about220 ppm. The source of nitric oxide containing gas may be a pressurizedcylinder containing nitric oxide gas. In several methods, the volume ofnitric oxide containing gas nasally delivered substantially equals thevolume of gas that fills the nasopharynx of the mammal. In othermethods, the rate of the delivering of the nitric oxide containing gasis about 1 liter per minute.

Delivery may be accomplished by bolus or pulse injections, and a seriesof injections over a period of time may be supplied to suitably bathethe nasopharynx with a therapeutic amount of NO containing gas.

The delivery may be controlled in that it occurs when the soft palate ofthe mammal is in a closed position. The closing of the soft palate maybe induced by a resistive element in communication with the oral cavityof the mammal.

The mammal may nasally inhale from a controllable reservoir of nitricoxide containing gas. This reservoir may have a volume that issubstantially equal to the volume of a mammal's nasopharynx. Thereservoir may be connected to a nasal mask or nasal insert prongs fordelivery to the mammal.

Several nasal delivery devices are herein described. Delivery may beaccomplished through a nasal device, wherein one nostril of the mammalreceives the nitric oxide containing gas while the other nostril of themammal is fitted with a one-way valve. Such devices may include nasalinsert prongs, mouthpieces, tubing, control valves, NO containing gassource and/or nasal masks.

In one embodiment, a nasal delivery device for controllably delivering anitric oxide containing gas to an upper respiratory tract of a mammalmay include: (1) a source of nitric oxide containing gas; (2) a nasalinterface adapted to provide fluid communication between the source ofnitric oxide containing gas and a first nostril of the mammal; (3) aflow-control valve for controlling the flow of the nitric oxidecontaining gas from the source to the mammal; (4) a one-way valveoperable to be inserted into a second nostril of the mammal; and (5) amouthpiece comprising a resistive element operable to close the softpalate of the mammal.

The nasal delivery device may also include a pressure monitor operableto detect a pressure within an oral cavity of the mammal. The supplyunit of the nasal delivery device may blend a source gas with compressedair to obtain the gaseous substance to be delivered. The nasal deliverydevice may include an analyzer to detect ambient or delivered levels ofa gaseous concentration. The nasal delivery device may deliver about 1liter per minute of the gaseous substance. The one-way valve mayrestrict inward flow upon delivery of the gaseous substance and allowthe gaseous substance to exit the upper respiratory tract.

Another nasal delivery device for controllably delivering a nitric oxidecontaining gas to an upper respiratory tract of a mammal may include:(1) a collapsible reservoir comprising nitric oxide containing gas andhaving a volume substantially equal to the volume of the nasopharynx ofthe mammal; (2) a nasal interface adapted to provide fluid communicationbetween a nose of the mammal and the collapsible reservoir; and (3) acontrol valve for controlling the delivery of the nitric oxidecontaining gas from the collapsible reservoir to the nasal interface.The nasal interface may be either a nasal mask operable to be placedaround the nose of the mammal or a nosepiece operable to be insertedinto at least one nostril of a mammal. The collapsible reservoir mayhold about 20 mL to about 50 mL of nitric oxide containing gas.

Another nasal delivery device for controllably delivering a gaseoussubstance to an upper respiratory tract of a mammal, may include: (1) asource of breathable gas connected via tubing to a nasal interface forproviding a gas stream of breathable gas to the mammal nasally; (2) aninspiration flow profile sensor that measures the inspiration flowprofile of the inspiration breath of the mammal; (3) a source of nitricoxide containing gas operably in fluid communication with the gas streamof the breathable gas; (4) a flow controller located between the sourceof nitric oxide containing gas and the gas stream for releasing nitricoxide containing gas to the nasal interface; and (5) a controller fortriggering the release of nitric oxide containing gas to the nasalinterface at a predetermined time close to the end of the mammal'sinspiration and at a flow rate that confines the nitric oxide containinggas in the upper respiratory tract of the mammal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the delivery of nitric oxide containing gas to theupper respiratory tract of a human subject.

FIG. 2 is a top cross sectional view of a human head, illustrating theflow of nitric oxide containing gas bathing the nasal cavities,according to one embodiment of the present invention.

FIG. 3 illustrates an embodiment of another device to deliver NOcontaining gas to the upper respiratory tract of a patient.

FIG. 4 illustrates an embodiment of another device to deliver NOcontaining gas to the upper respiratory tract of a patient.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particular devices,compositions, methodologies or protocols described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims.

Although any methods, devices, and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments of the present invention, the preferred methods, devices,and materials are now described. All publications mentioned herein areincorporated by reference. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention. As used herein, terms such as “subject,”“patient,” and “mammal” may be used interchangeable.

The nasal airway is comprised of two nasal cavities separated by thenasal septum and includes numerous ostia, such as the paranasal sinusostia and the tubal ostia, and olfactory cells. The nasal airway cancommunicate with the nasopharynx, also described as the upper throatarea, the oral cavity, and the lower airway, with the nasal airway beingin selective communication with the anterior region of the nasopharynxand the oral cavity by opening and closing of the oropharyngeal velum,or often referred to as the soft palate. The closing of the soft palateis achieved by providing a certain positive pressure in the oral cavity,such as achieved on exhalation through the oral cavity against aresistive element.

The methods described herein provide nasal delivery of a nitric oxidecontaining gas to the upper respiratory tract including the nasopharynx.By use of the term “upper respiratory tract,” Applicants are referringto the area defined from the entrance of the nostrils to the softpalate, the area including the nasal cavities, sinuses and nasopharynx.The methods and devices described herein controllably deliver the nitricoxide containing gas nasally. By “controllably”, it is meant that thenitric oxide containing gas is confined to the upper respiratory tractof the mammal.

The methods for controllably delivering nitric oxide containing gas tothe upper respiratory tract may be achieved by a number of differentways. For example, the delivery of nitric oxide gas may be timed with anasally inhaled gas stream such that it is delivered only at the end ofthe subject's inhalation. This timing of nitric oxide containing gasdelivery causes the nitric oxide containing gas to reach only the upperrespiratory airway, and not further into the respiratory system.Alternatively, the oropharyngeal velum or soft palate may be induced toclose to seal the upper respiratory airway from the rest of the lowerrespiratory system, including the lungs. Delivery of nitric oxidecontaining gas can then be made to this sealed upper respiratory airway.One way to induce closing of the soft palate is through the naturalexhalation of the subject through the mouth against partially closedlips. Preferably, a resistive element is provided to the subject's mouthsuch that more precise increases in pressure in the oral cavity isprovided.

Because NO containing gas is only delivered to the upper respiratorysystem, there are minimal toxicity concerns in using the contemplatedtherapeutic concentrations of nitric oxide gas (such as 160 ppm to 400ppm). Previous delivery methods for gaseous NO to a patient have allowedthe NO containing gas to flow directly or indirectly into the lungs. Inthe present applications, since the NO containing gas does not reach thelungs, there is less absorption of the nitric oxide into the bloodstream to form methemoglobin. Concern about damage to the lungsresulting from conversion of NO to NO₂ is also decreased.

Accordingly, concentrations greater than 100 ppm nitric oxide and, morepreferably, greater than 160 ppm nitric oxide may be safely bathe theupper respiratory tract of a subject. Preferably, the concentration ofnitric oxide in the nitric oxide containing gas in the upper respiratorytract is about 120 ppm to about 400 ppm, more preferably, about 160 ppmto about 220 ppm.

Preferred Delivery During Exhalation

In one embodiment, NO containing gas may be nasally delivered to asubject during exhalation. As seen in FIG. 1, this method uses exhalingthrough the mouth against a resistive element 2 to close the soft palate1, sealing the nasopharynx from the rest of the lower respiratorysystem. While a patient exhales through the oral cavity, a flow-controlvalve may then be opened to administer the NO containing gas from anitric oxide gas source through one of the nostrils of the patient.Since the soft palate is closed (by the mechanism of exhalation), thisdelivery of NO containing gas is confined to the upper respiratory tractincluding the closed or sealed nasopharynx.

A pressure monitor 7 for monitoring the oral cavity may also beprovided. Once a pressure monitor of a resistor element (monitoring theoral cavity pressure and thus the position of the soft palate) ispresent (and reaches a threshold such as about 5 cm H₂O), the flow of NOcontaining gas may begins. The flow of NO containing gas is preferablydelivered through one nostril using a nasal interface comprising a valve6 while the other nostril may be sealed with a one-way flow out valve 15(FIG. 2). The pressure of the delivered NO gas may be just aboveatmospheric, such as about 1-4 cm H₂O. The pressure of the NO gashowever should be lower than about 5 cm H₂O, so that the soft palateremains in a closed position. The one-way valve 15 seals the nostrilfrom inhaling air, and thus, prevents outside air from carrying the NOcontaining gas in the nasopharynx into the lungs. However, air and NOcontaining gas are allowed to exit through the one-way valve 15.

As seen in FIGS. 1 and 2, blocking one nostril creates a controlledsystem wherein the NO containing gas bathes the closed nasopharynx andthe nasal cavity of the patient, before it exits through the one-wayvalve. These delivery systems cause the nitric oxide gas to enter intoone nasal cavity, flow around the posterior margin into the sealednasopharynx 11, out of the nasopharynx, and out the other nasal cavity.The flow of the NO containing gas is represented by the reference number10 in FIGS. 1-3.

The exit of the NO containing gas through the one-way valve 15 may beinto the atmosphere. Because the volume of NO containing gas isrelatively small (about 1 liter per minute), allowing this gas to beexited freely into the atmosphere does not create a substantial risk ofharm to the patient and surrounding environment. Ambient concentrationsof nitric oxide or nitrogen dioxide resulting from the use of a deliverysystem is estimated at about 50 ppb. To illustrate the safety of theexiting NO containing gas, a comparison to the concentration of nitricoxide in cigarette smoke may be appropriate. It is estimated that asimilar volume of exhaled cigarette smoke contains about 150 ppm of NO.Therefore, allowing the exit of the NO containing gas into theatmosphere through the one-way valve 15 is significantly less harmful,than exhaled cigarette smoke released into the atmosphere.

Still referring to FIGS. 1 and 2, the one-way valve 15 also acts toprevent NO containing gas to enter the lower respiratory tract 9. Apatient is unable to inhale air back through the one-way valve 15.Therefore, once the NO containing gas is turned off, and the NOcontaining gas is bathing the upper respiratory tract, there is littlerisk of this gas reaching the lungs. If the patient inhales through itsmouth while the NO containing gas is within the upper respiratory tract,and thus opens the soft palate 1, the NO containing gas will not flowinto the lower respiratory tract from the upper respiratory tractbecause there is no flow of air into the nasal cavity to displace the NOcontaining gas. The only pathway for gas entrance into the lungs isthrough the oral cavity. This pathway is represented by the referencenumber 8 in FIG. 1. Thus, a patient's inhalation will be oral and theabsence of nasal flow will contain the NO containing gas in the upperrespiratory area. Because there is no nitric oxide delivery through theoral cavity, no nitric oxide enters the lungs during this patientinhalation.

FIG. 1 further illustrates a nasal delivery device which may be used tonasally deliver the NO containing gas while a subject is exhaling. Thisdevice may include a nasal interface 6 for fitting to a nostril of asubject, a one-way valve 15 to block the outlet nostril of a subject, amouthpiece 2 through which the subject in use exhales and that includesa resistive element, and a NO gas source 3 and control unit 4 forregulating and monitoring the concentration and flow of nitric oxidegas. Additionally, a pressure monitor 7 may also be provided (eitherintegral to the NO control unit 4 or as a separate unit) to monitor thepressure of the oral cavity. The NO delivery unit is preferably computercontrolled via a controller such as a microprocessor. However, discreteelectronic or pneumatic components could accomplish the same objective.Logic (either through firmware or software) may be programmed in orderto control the delivery of NO such that delivery of NO gas from the NOgas source is triggered when the oral cavity reaches a certain thresholdpressure, as measured by the pressure monitor. Thus, the pressuremonitor provides feedback to the delivery unit as to when the NO gas isto be released into the nasal airway. If the pressure in the oral cavitydrops below the threshold, then the soft palate is no longer closed andthe logic is programmed to stop the NO gas flowing into the nasalcavity.

Still referring to FIG. 1, the NO gas source 3 may be a pressurizedcylinder containing NO gas. Appropriate systems and methods for storingand using NO containing gas, diluting it to effective concentrations andchanneling it to a delivery device are known in the art, and aredescribed, for example, in U.S. Pat. Nos. 6,793,644 and 6,581,599, whichare hereby incorporated by reference as if fully set forth herein. Thesesystems and methods may be used with any delivery device describedherein.

While the use of a pressurized cylinder is the preferred method ofstoring the NO containing gas source, other storage and delivery means,such as a dedicated feed line (wall supply) can also be used. The NOcontaining gas may be adjusted for NO concentration by use of a diluentgas as described in U.S. Pat. No. 6,793,644 or the NO containing gas maybe supplied in its desired concentration without the need for dilution.The source of diluent gas may contain N₂, O₂, Air, an inert gas, or amixture of these gases. The source of diluent gas may be stored within apressurized cylinder or provided by a simple air pump. For example,compressed clean, dry air at 50 psig may be blended with the NO sourcegas. Both the NO gas source and the diluent source may include internalor external filters, such as a particulate filter, a watertrap filter,or a combination thereof. Because the topically applied gas is notinhaled, there is no need for it to contain oxygen as one of itscomponents.

The NO gas from the NO gas source 3 and the diluent gas from the diluentgas source preferably pass through pressure regulators to reduce thepressure of gas that is admitted to the control unit 4 and delivered tothe subject. The respective gas streams may also pass via tubing to anoptional gas blender to mix the respective gases. The NO containing gasmay be output from the gas blender and travel via tubing to a flowcontrol valve, preferably contained in the control unit 4. The flowcontrol valve may include, for example, a proportional control valvethat opens (or closes) in a progressively increasing (or decreasing ifclosing) manner. As another example, the flow control valve may includea mass flow controller. The flow control valve controls the flow rate ofthe NO containing gas that is introduced to the nasal interface 6. TheNO containing gas leaves the flow control valve via flexible tubing. Theflexible tubing attaches to an inlet in the nasal interface 6.

Additionally, NO and NO₂ analyzers, which are known in the art, may alsobe incorporated into the control unit 4 to monitor the NO and NO₂concentration of the gas delivered to the subject's upper respiratorytract.

The nasal interface 6 may include one nasal insert prong that fits intoone of the nostrils of the patient, providing a tight sealing fit. Thenasal insert prong may be oval or cylindrical in shape, may include aflange design to hold the insert within the nostril, and may be shapedto fit coaxially within the nostril of a patient. Such a suitable nasalinsert prong may be the nasal inserts described for use in the LYRA®Interface, available from VIASYS Healthcare Inc., Conshohocken, Pa. Anappropriate nasal interface is one that is made of a soft, flexiblematerial and provides an effective sealing of the nostril. In additionto insert prongs, a nasal pillow of other suitable design may be used.The nasal interface 6 may be formed of a resilient material such as apolymeric or silicone elastomer material. The nasal interface 6 mayinclude an optional one-way valve that prevents the backflow of gas intothe tubing. The other nostril of a patient may be fitted with a one-wayflow-out valve 15 to control the targeted delivery of the NO containinggas to the sealed upper respiratory tract. This one way flow-out valve15 may also be constructed as an integral part of the nasal interface oras a separate piece from the nasal interface.

When the patient breathes out through a mouthpiece 2 and a positivepressure in the oral cavity is maintained such as to seal the softpalate in a closed position. The sealed soft palate creates an isolatednasopharynx such that NO gas may not enter the rest of the respiratorytract. Various methods and devices may be used to create the positivepressure in the oral cavity and seal the soft palate. Such methods anddevices are generally described in U.S. Pat. Nos. 6,067,983; 6,715,485;U.S. Publication No. 2004/0149289, and U.S. Publication No.2004/0112378, each herein incorporated by reference in their entirety.In order to close the soft palate, a positive pressure differentialshould be established between the oral cavity and the nasal airway. Thispressure differential is about 5 cm H₂O to about 10 cm H₂O. In order tocreate the necessary pressure in the oral cavity, various resistiveelements may be employed. The resistive element may be preferably placedon the expiratory port so that there is no resistance to breathing airinto the lungs. The mouthpiece 2 may include this resistive element,which may be, for example, one or more baffle plates or an absorbingfilter to absorb bacteria or viral agents. The mouthpiece 2 may alsoallow a patient to inhale and exhale through the oral cavity, using theambient atmosphere as the air supply, or any other source of breathableair. The mouthpiece 2 may be made of any suitable material, such as apolymeric material.

Referring to FIG. 3, a subject places the mouthpiece 2 in his/her lipsand fits the nasal interface 6 into one of his/her nostrils, while theoutlet nostril is fitted with the one-way valve 15. The subject thenexhales through the mouthpiece 2, the flow of which exhaled air isresisted by the resistive element such as to develop a positive pressurein the oral cavity of the subject sufficient to cause closure of thesoft palate. The exhaled air, after passing over the resistive element,then may mix with ambient air via an outlet 12. Alternatively,mouthpieces may be designed to attach to an artificial air source, as areservoir or a ventilator. Again, reference number 10 refers to the NOcontaining gas flow. The nasal interface 6 is connected to the controlunit 4 via appropriate tubing 13.

A pressure monitor 7 may be operably connected with the mouthpiece todetermine the oral cavity pressure. This pressure monitor providesappropriate signals to the controller for controlling the opening andclosing of the control valve for the flow of NO containing gas to thenasal interface 6. The triggering event for opening the flow of NOcontaining gas to the nasal interface 6 preferably occurs when the oralcavity pressure is about 5 cm H₂O.

Suitable therapeutic volumes of NO containing gas may be delivered to apatient. For example, a total gaseous flow rate may be about 1 liter perminute. For example, if NO is first blended with air, the NO gas flowingfrom the NO gas source may be about 0.2 liter per minute, while thecompressed air flow may be about 0.8 liter per minute. Since theinjection of NO containing gas to the nasal interface is controllablytimed to correlate with an exhalation event, the flowrate of about 1liter per minute may not be a continuous flowrate, but rather representsthe rate of the pulsed injection. Each pulse injection therefore, maylast for about 1 to about 5 seconds. The injections may also beconsecutive for about 3 to about 60 minutes.

Preferred Delivery During Inhalation

Another device for the nasal delivery of NO during inhalation isillustrated in FIG. 4. In this device, a nasal interface 16 (such as anasal mask or nasal insert prongs) is provided to interface with thenose of a subject, while leaving the mouth unobstructed. On one side ofthe nasal interface 16 is a valve 17 that may connect the nasalinterface 16 to a collapsible gas reservoir 18 capable of holding asmall volume of gas. The volume of the gas reservoir 18 may besubstantially equal to the nasopharynx volume or another suitabletherapeutic volume of NO containing gas. This volume is estimated atabout 20 to about 50 mL for an adult human patient. When the valve 17opens, the patient may nasally inhale the amount of gas from thereservoir 18, which is only enough to fill the patient's nasopharynx.This volume may also be forced into the nasal passage through manuallysqueezing the collapsible reservoir or through another suitable force orpressure-based flow. The reservoir may be filled directly from apressurized gas tank containing NO gas, or may be replenished with theNO containing gas by using a small pressurized canister 19 that injectsa fixed volume on each injection. A fill port 20 connected to the valve17 may have a one-way check valve that allows gas to enter thereservoir.

Using this device, the patient may freely breathe through her mouthwithout obstruction, but will not inhale the NO containing gas past thenasopharynx because of the controlled volume of NO containing gas beingdelivered through use of the reservoir.

If the patient exhales through her nose, only that amount of gas thatwas in the nasopharynx will re-fill the reservoir 18. Thus, the nasalcavities, nasopharynx and sinuses, will be bathed in the NO containinggas in this delivery method. The patient may also recycle the NOcontaining gas from the reservoir 18 to the nasopharynx through thismask-reservoir system for a period of time, such as about 5 minutes toabout 60 minutes. A suitable series of deliveries over a period of timemay be suitable to bathe the upper respiratory tract including thenasopharynx with a therapeutic amount NO containing gas.

In another embodiment, delivery of nitric oxide gas to the upperrespiratory tract may be achieved through delivery that is coincidentalwith the inhalation of the subject. Breathable air from any source(e.g., ambient room air or ventilator carrying oxygen containing gas)may be directed to a nasal interface using techniques well known in theart. The inspiration and expiration flow rates of a spontaneous nasalbreathing of a patient may be monitored using a flow sensor known in theart and, inspiration flow profiles can be determined for the patient'sbreathing. Inspiration flow profile of the breathable gas is the flowrate of the gas as a function of inspiration time. Nasal delivery of theNO containing gas, preferably added to the breathable gas stream througha Y-piece connector, may be timed to coincide with the end of patient'snasal inspiration.

During the early part of the subject's breath, the inhaled gas containsno nitric oxide. As the subject ends its inspiration, the NO containinggas is injected into the gas stream so that the NO containing gas isinhaled through the nasal cavity to the nasopharynx. The timing of thisinjection may be accomplished by waiting until after the inspiratoryflow rate reaches a maximum and returns close to zero flow. Once apredetermined threshold on the deceleration of an inhalation is reached,the NO containing gas stream may be initiated and added through theY-piece connector. The timed delivery based on a patient's inspiratoryflow profile and the device for performing such delivery is exemplifiedand described in U.S. Pat. No. 6,581,599 issued to one of the applicantsand is incorporated by reference in its entirety as if fully set forthherein.

In the embodiments described to deliver the nitric oxide containing gasat the end of an inspiration, the concentration of the gas delivered maybe slightly higher than the desired concentration for therapeuticeffectiveness to account for the dilution by the breathable air flowinginto the nose. For example, therapeutic concentrations of nitric oxidein the nitric oxide containing gas may be about 160 to 400 ppm. In orderto meet the therapeutic level in certain embodiments, a deliveryconcentration of the nitric oxide should be increased by about 10percent to account for dilution with breathable gas. For example, thedelivery gas should contain concentrations of nitric oxide of about 175to 440 ppm. These values of nitric oxide containing gas may be deliveredto a patient near the end of their inspiration, wherein the patient isbreathing at a flow rate of about 1 liter per minute. For example,delivered nitric oxide containing gas having a concentration of about200 ppm at 9 liter per minute would be reduced to a concentration ofabout 180 ppm in the upper respiratory tract when diluted by thebreathable air. As another example, a pulse of about 0.3 to 0.5 secondsof nitric oxide would deliver 50 to 80 milliliters of nitric oxide intothe nose at a volume sufficient to fill only the nasopharynx.

Alternative triggering of the NO flow into the breathable gas stream canalso be accomplished by measuring and modeling the patient's inspirationprofile for a number of previous breaths. NO flow is then initiated on asubsequent breath based upon a predicted timing of the patient'sbreathing to flow NO only at the end of inspiration so that only thenasopharynx is filled. Yet another alternative method of determining thepoint to initiate the NO flow is by measuring the volume inspired by thepatient, which can be calculated based on the flow rate and elapsed timeof flow of the breathable gas. At the volume before reaching the end ofinspiration whereby the NO flow would fill the nasopharynx, the NO gaswould then begin its flow.

The above methods are preferably performed through the use of a controlmodule, preferably a controller such as a computer microprocessor withassociated logic (firmware or software), that may time the release ofthe nitric oxide containing gas to the nasal interface. The timing maybe at the end of the mammal's inspiration, at a predetermined orpremeasured time. Alternatively, the patient's inspiratory flow orvolume may be measured and thus delivery will coincide with thismeasurement. In any timed delivery, the volume of NO containing gas isabout equal to the patient's nasopharynx. This volume may be monitoredor adjusted based on successive breaths.

In another embodiment, a pulse dose delivery or a bolus injectiondelivery of the NO containing gas may be used. The timing of the bolusinjection may be correlated to the detection of a patient breath. Once apredetermined time has passed from breath detection, a bolus injectionof the NO containing gas may be delivered to the upper respiratorytract.

In the inhalation methods of delivery, the NO containing gas is mixed orinjected into the gas stream that is being nasally inhaled by a subject.By contrast, in the exhalation methods described above, the patient isbreathing through its mouth. The nasal delivery of the NO containing gasmay be “artificial” or forced, such as delivered through a pressurizedsystem through the nostril(s) into the upper respiratory tract. In theinhalation methods of delivery, the patient will not inhale the NOcontaining gas past the nasopharynx because of the controlled injectionof NO containing gas. Hence, through the targeted delivery of the NOcontaining gas, the NO containing gas will only bathe and contact theupper respiratory system of the subject. Accordingly, there is little orno risk that the NO containing gas will reach beyond the nasopharynxinto the lungs of the subject.

Devices to accomplish delivery methods during inhalation that aredescribed above may include a delivery unit comprising a nasal interface(such as a nasal mask or nasal insert prongs) for fitting to a nostrilof a subject, a source of breathable gas, and a nitric oxide containingsource, and a control unit for delivering the gas. NO containing gassource may be a pressurized cylinder containing NO containing gas. Afterbeing optionally adjusted for delivery concentrations and pressure, theNO containing gas passes through tubing to a flow control valve. Theflow control valve, which preferably is electronically controlled by thecontrol unit, controls injection or addition of the NO containing gasinto the gas stream flowing from the source of breathable gas to thenasal interface fitting into the nostril of a subject. The patient isallowed to nasally inhale and exhale this air from the air source,subject to the timed injection of the NO containing gas upon inhalation.

Upon timing with the patient's breathing or at a measured volume of theinspiration profile, the flow control valve opens and a jet of NOcontaining gas is added to breathable gas stream to be included as partof an inhalation.

The device may further include NO and NO₂ analyzers, that are well knownin the art, to monitor the concentration of nitric oxide or nitrogendioxide. Other safety devices known in the art such as NO₂ scavengersfor exhaled gas may also be incorporated into the delivery devicesdescribed herein.

The NO containing gas may be dosed in several ways to supply atherapeutic amount. By the term “therapeutic amount” is meant, forpurposes of the specification and claims, to refer an amount sufficientto kill or inhibit microorganisms in the upper respiratory tract. Aflowrate of about 1 liter per minute of about 160 ppm nitric oxide toabout 400 ppm nitric oxide may effectively decontaminate the upperrespiratory tract of a subject. Therefore, about 1 liter per minute ofabout 160 ppm nitric oxide to about 400 ppm nitric oxide may bedelivered to patients. Additionally, delivered gases having a slightlyhigher nitric oxide concentration, such as about 175 ppm to about 440ppm, may be delivered to patients. These slightly higher concentrationsaccount for dilution with breathable gas as explained above in theinhalation methods. Other suitable parameters for delivery, dosage, orNO exposure may be found in U.S. Pat. Nos. 6,793,644 and 6,432,077. Inany delivery method, NO containing gas may be by bolus injection, or bypulse injection, systematically, for a period of time. Such suitableexposure times may be, for example, about 3 minutes to about 60 minutesof total NO exposure time.

Microcidal Effects of NO Gas

The delivery of a NO containing gas nasally to an upper respiratory areaof a mammal may topically decontaminate the upper respiratory tract ofmicroorganisms, such as viruses, bacteria, mycobateria, parasites, andfungi. This decontamination may be an effective treatment ofnasopharyngeal infections and upper respiratory infections. While thedelivery of the NO containing gas is isolated to the upper respiratorysystem including the nasopharynx, the decontamination of the upperrespiratory tract of microorganisms greatly reduces risk of thespreading of infection to the lower respiratory tract and provides apreventative treatment of the respiratory system as a whole, includingthe lungs.

The dominant mechanism(s) whereby NO, known to be produced in responseto stimulation of the calcium-independent inducible nitric oxidesynthase, results in intracellular killing of mycobacteria has beendescribed in U.S. patent application Ser. No. 09/762,152

Additionally, viruses may be susceptible to nitric oxide. While notwishing to be bound by theory, it appears that viruses may besusceptible to nitric oxide due to their unsophisticated detoxificationpathways. Several possible mechanisms exist to explain the cidal andinhibitory effects of NO on viruses. First, metal ion based DNAdeamination may be linked to the cidal effectiveness. NO may also play adominant role in destructive hydroxyl radical formation. NO mayinterfere with viral replication through RNA reductase inhibition. NOmay interfere with Hemagglutinin protein synthesis. NO may alsointerfere with virion release or maturation. Upon exposure to NO,infected cells exhibit reduced virion RNA release.

Several researchers have documented the antiviral effects of the NOmolecule produced chemically by NO donors. For example, cells infectedwith influenza virus A/Netherlands/18/94 were treated with NO, anexperiment described in Rimmelzwaan, et. al., “Inhibition of InfluenzaVirus Replication by Nitric Oxide,” J. Virol. 1999; 73:8880-83, hereinincorporated by reference in its entirety. Results show theeffectiveness of NO as a preventive therapy to viral agents.Additionally, a study by Sanders, et. al. demonstrates the effectivenessof naturally produced NO by the body as an antiviral agent, particularlyagainst human rhinovirus. See Sanders, et. al., “Role of Nasal NitricOxide in the Resolution of Experimental Rhinovirus Infection,” J.Allergy Clin, Immunol. 2004 April; 113(4):697-702, herein incorporatedby reference in its entirety.

Nasal Resistance Testing Following NO Exposure

Nitric oxide is known to have several biophysical properties, of whichtwo important ones are its relaxation effects on blood vessels and itsability to kill microorganisms. With the approach of using exposure ofthe nasopharynx to NO gas to kill microorganisms was the question ofwhether it would have an adverse effect on the vascular tone of thenasal vessels that might preclude its therapeutic use because it mightdilate the vessels and obstruct the nasal passage.

To test for this untoward effect, a normal volunteer was treated with160 ppm NO gas using one of the methods described (1 liter per minuteflowed up one nostril and out the other through a check valve duringsubject exhalation against a 5 cm H₂O resistor) for 15 minutes. Prior tothe treatment, baseline measurements of right and left nasal resistancewere performed using a Jaeger rhinometer. The rhinometer measures thedifferential pressure across each of the nostrils being tested with apressure sensor port measuring the pressure at the entrance of thenostril being tested and by occluding the non-tested nostril withpressure sensing line, measures the pressure at the back of the opennostril being tested. Each nostril was tested separately.

Following the 15 minute exposure, resistance of each nostril wasmeasured and again at 30 minutes. The results of that experimentdemonstrated that there was no change in overall nasal resistance andthat the changes within each nostril was less than what is consideredclinically significant and that the changes follow the normal diurnalvariation between higher and lower resistances of the nasal passages.This supports that the NO produced no changes to nasal vasculature thatwould effect resistance to airflow.

While embodiments of the present invention have been shown anddescribed, various modifications may be made without departing from thescope of the invention. The invention, therefore, should not be limited,except to the following claims, and their equivalents.

1. A nasal delivery device for delivering nitric oxide containing gas to an upper respiratory tract of a mammal, said device comprising: a source of nitric oxide containing gas; a nasal interface adapted to provide fluid communication between the source of nitric oxide containing gas and a first nostril of the mammal; a flow-control valve for controlling the flow of the nitric oxide containing gas from the source to the mammal; a one-way valve operable to be inserted into a second nostril of the mammal; and a mouthpiece comprising a resistive element operable to close the soft palate of the mammal.
 2. The nasal delivery device of claim 1, wherein the nasal interface comprises a nosepiece operable to be inserted into the first a nostril of a mammal.
 3. The nasal delivery device of claim 1, further comprising a pressure monitor operable to detect a pressure within an oral cavity of the mammal.
 4. The nasal delivery device of claim 3, further comprising a controller with logic such that the flow control valve is opened when a threshold pressure is detected in the oral cavity of the mammal.
 5. The nasal delivery device of claim 3, wherein the pressure monitor is operably connected to the mouthpiece.
 6. The nasal delivery device of claim 1, further comprising a gas blender.
 7. The nasal delivery device of claim 1, wherein the supply unit further comprises an NO analyzer.
 8. The nasal delivery device of claim 1, wherein the supply unit is operable to deliver about 1 liter per minute of the nitric oxide containing gas.
 9. The nasal delivery device of claim 1, wherein the one-way valve is operable to restrict inward flow upon delivery of the nitric oxide containing gas.
 10. The nasal delivery device of claim 1, wherein the one-way valve is operable to allow the nitric oxide containing gas to exit the upper respiratory tract.
 11. The nasal delivery device of claim 1, wherein the resistive element operable to provide at least about 5 cm H₂O pressure in an oral cavity of the mammal.
 12. The nasal delivery device of claim 1, further comprises a collapsible reservoir.
 13. The nasal delivery device of claim 12, wherein collapsible reservoir has a volume that is substantially equal to the volume of the upper respiratory tract of the mammal.
 14. The nasal delivery device of claim 13, wherein the volume of the collapsible reservoir is about 20 mL to about 50 mL.
 15. A nasal delivery device for delivering a nitric oxide containing gas to an upper respiratory tract of a mammal, said device comprising: a collapsible reservoir comprising nitric oxide containing gas and having a volume substantially equal to the volume of the upper respiratory tract of the mammal; a nasal interface adapted to provide fluid communication between a nose of the mammal and the collapsible reservoir; and a control valve for controlling the delivery of the nitric oxide containing gas from the collapsible reservoir to the nasal interface.
 16. The nasal delivery device of claim 15, wherein the volume of the collapsible reservoir ranges from about 20 mL to about 50 mL.
 17. The nasal delivery device of claim 16, further comprising a fill port for filling the collapsible reservoir with nitric oxide containing gas from a source of nitric oxide gas.
 18. The nasal delivery device of claim 15, wherein the nasal interface is a nasal mask operable to be placed around the nose of the mammal.
 19. The nasal delivery device of claim 15, wherein the nasal interface is a nosepiece operable to be inserted into at least one nostril of a mammal.
 20. The nasal delivery device of claim 19, wherein the nosepiece comprises an insert operable to seal the nostril of the mammal.
 21. A nasal delivery device for delivering a nitric oxide containing gas to an upper respiratory tract of a mammal, the device comprising: a source of breathable gas connected via tubing to a nasal interface for providing a gas stream of breathable gas to the mammal nasally; an inspiration flow profile sensor that measures the inspiration flow profile of the inspiration breath of the mammal; a source of nitric oxide containing gas operably in fluid communication with the gas stream of the breathable gas; a flow controller located between the a source of nitric oxide containing gas and the gas stream for releasing nitric oxide containing gas to the nasal interface; a controller for triggering the release of nitric oxide containing gas to the nasal interface at a predetermined time close to the end of the mammal's inspiration and at a flow rate that confines the nitric oxide containing gas in the upper respiratory tract of the mammal.
 22. The nasal delivery device of claim 21, wherein the predetermined time is a time after the inspiratory flow rate reaches maximum and returns to close to a zero inspiratory flow rate.
 23. The nasal delivery device of claim 21, wherein the nasal interface is a nosepiece operable to be inserted into at least one nostril of the mammal. 